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Impaired PPARγ activation by cadmium exacerbates infection-induced lung injury
Jennifer L Larson-Casey1, Shanrun Liu2, Jennifer M Pyles3
1Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine.
Abstract:
Emerging data indicate an association between environmental heavy metal exposure and lung disease, including lower respiratory tract infections (LRTIs). Here, we show by single-cell RNA sequencing an increase in Pparg gene expression in lung macrophages from mice exposed to cadmium and/or infected with Streptococcus pneumoniae. However, the heavy metal cadmium or infection mediated an inhibitory posttranslational modification of peroxisome proliferator-activated receptor γ (PPARγ) to exacerbate LRTIs. Cadmium and infection increased ERK activation to regulate PPARγ degradation in monocyte-derived macrophages. Mice harboring a conditional deletion of Pparg in monocyte-derived macrophages had more severe S. pneumoniae infection after cadmium exposure, showed greater lung injury, and had increased mortality. Inhibition of ERK activation with BVD-523 protected mice from lung injury after cadmium exposure or infection. Moreover, individuals residing in areas of high air cadmium levels had increased cadmium concentration in their bronchoalveolar lavage (BAL) fluid, increased barrier dysfunction, and showed PPARγ inhibition that was mediated, at least in part, by ERK activation in isolated BAL cells. These observations suggest that impaired activation of PPARγ in monocyte-derived macrophages exacerbates lung injury and the severity of LRTIs.
Insights
Environmental heavy metal exposure, like cadmium, worsens lung infections by inhibiting PPARγ (peroxisome proliferator-activated receptor gamma) in lung macrophages. This pathway exacerbates lung injury and increases infection severity.
Area of Science:
- Environmental Health
- Immunology
- Molecular Biology
Background:
- Emerging evidence links environmental heavy metal exposure to lung diseases, including lower respiratory tract infections (LRTIs).
- Lung macrophages play a critical role in the immune response to infection and environmental insults.
Purpose of the Study:
- To investigate the role of peroxisome proliferator-activated receptor gamma (PPARγ) in cadmium-induced exacerbation of LRTIs.
- To elucidate the molecular mechanisms by which cadmium and infection impact PPARγ activity in lung macrophages.
Main Methods:
- Single-cell RNA sequencing was used to analyze gene expression changes in lung macrophages.
- Experiments involved mouse models of Streptococcus pneumoniae infection and cadmium exposure.
- ERK activation and PPARγ degradation were assessed in monocyte-derived macrophages.
- Pharmacological inhibition of ERK activation was tested.
- Human bronchoalveolar lavage (BAL) cells from individuals in high cadmium areas were analyzed.
Main Results:
- Cadmium exposure and S. pneumoniae infection increased Pparg gene expression but led to inhibitory posttranslational modification of PPARγ.
- Both cadmium and infection increased ERK activation, promoting PPARγ degradation in macrophages.
- Mice with PPARγ deletion in macrophages showed exacerbated infection, lung injury, and mortality after cadmium exposure.
- Inhibition of ERK activation protected mice from lung injury.
- Human subjects in high cadmium areas exhibited increased BAL fluid cadmium, barrier dysfunction, and ERK-mediated PPARγ inhibition.
Conclusions:
- Impaired PPARγ activation in monocyte-derived macrophages exacerbates lung injury and LRTIs severity.
- ERK activation is a key mediator of cadmium- and infection-induced PPARγ inhibition.
- Targeting the ERK-PPARγ pathway may offer therapeutic strategies for heavy metal-associated lung diseases.
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